Olefin metathesis is an efficient reaction for the formation of carbon-carbon bonds by exchanging substituent groups on two olefin reactants. Certain ruthenium catalysts have helped to increase the practicality of using olefin metathesis for organic synthesis due to modified functional groups that have increased their tolerance to air and moisture. However, highly active catalysts can be sensitive to some polar functional groups, while catalysts that are more highly stable to polar functional groups can have diminished activity. Therefore, improved catalysts that are more highly stable to functional groups while retaining substantially undiminished activity are needed, as well as improved processes that can utilize such catalysts. More active and more stable catalysts would broaden the practical utility of olefin metathesis use for organic synthesis, e.g., ring-closing and cross metathesis reactions of functionalized olefins using α,β-unsaturated carbonyl compounds.
I. Olefin Macrocyles and Derivatives
One field of organic synthesis that could benefit from improved yields using improved metathesis catalysts is the field of macrocyclization of olefins (and optional subsequent reaction or reduction of the double bonds), which is considered much more difficult than macro-lactonization and macro-lactamization. There is a need for an improved mild and efficient route for the production of carbocycles, particularly ring expansion of cyclic olefins without excessive side reactions, such as polymerization. U.S. Pat. No. 6,482,908 provides a method for producing olefin macrocycles from acyclic diene starting materials (such non-cyclic diene starting materials may be polymeric) by using ring-closing metathesis (“RCM”). Such RCM improved procedures addressed a problem in the art that had required the acyclic diene starting materials to be conformationally restrained in order to achieve acceptable yields. While overcoming some prior art problems, such a process did not provide a method for expanding existing cyclic olefins.
Macrocyclic compounds, such as cyclized olefins or functionalized cyclic molecules are important classes of compounds that are used extensively in the chemical industry, e.g., as metal-complexing species, or as cyclic alcohols for forming esters from organic acids to remove organic acids from solutions. These molecules have many uses including analytical chemistry titrations, forming esters, removal of ions from solutions and soils, iron binding in hemoglobin, magnesium binding in chlorophyll, and for medicinal uses such as antimicrobial agents against gram-positive bacteria, fungi, viruses and the like. One particularly useful class of functionalized cyclic molecules is crown ethers which also find important uses as solubilizers for metals in organic transformation reactions. See Crown Ethers and Analogs, Patai, S. and Rappoport, Z. Eds; John Wiley & Sons: New York, 1989, which is incorporated herein by reference and contains many examples of technically and scientifically important functionalized cyclic molecules including crown-ethers, crown-thioethers, porphyrins, lariats, cryptands, sandwich complexes and the like.
When the functionalized cyclic molecules contain a site of unsaturation, as in the case of functionalized cyclic olefins, the site of unsaturation may be used for further chemical modification of the molecule. Such modifications by include chemical addition reactions with the unsaturated bonds or by hydrogenation of the double bond. Carbonyl functional groups may be by reduction to alcohols that are capable of forming esters with acid groups. In addition, cyclic olefins may contain hetero atoms, e.g. ethers or amine groups. Also, the functionalized cyclic olefins may also be used as the starting materials for polymer or oligomer synthesis via a ring opening metathesis polymerization (“ROMP”) reaction. This is discussed further below, since ROMP of such functionalized cyclic olefins can provide an improved method for synthesizing functionalized polymers or oligomers which possess regularly spaced sites of unsaturation and regularly spaced functional groups.
There remains a need for new, improved or larger macrocycles, as well as improved methods (mild and efficient routes) for producing them, such as by a reliable and efficient olefin ring expansion process. But, such a process presents several formidable obstacles that must be overcome before achieving success. For example, cyclic olefins (e.g., cycloalkenes) must be able to undergo a ring-opening metathesis (“ROM”) reaction. Once opened, a cycloalkene must react selectively with an acyclic diene for cross metathesis (“CM”) to properly occur, and then must undergo a subsequent selective ring closure metathesis (“RCM”). Prior to the present invention such difficulties had not been overcome.
II. Transition Metal Carbene Complexes as Metathesis Catalysts
Transition metal carbene complexes, particularly ruthenium and osmium carbene complexes, have been described as metathesis catalysts in U.S. Pat. Nos. 5,312,940, 5,342,909, 5,831,108, 5,969,170, 6,111,121, and 6,211,391 to Grubbs et al., assigned to the California Institute of Technology. The ruthenium and osmium carbene complexes disclosed in these patents all possess metal centers that are formally in the +2 oxidation state, have an electron count of 16, and are penta-coordinated. Such complexes have been disclosed as useful in catalyzing a variety of olefin metathesis reactions, including ROMP, ring closing metathesis (“RCM”), acyclic diene metathesis polymerization (“ADMET”), ring-opening metathesis (“ROM”), and cross-metathesis (“CM” or “XMET”) reactions. Examples of such catalysts are (PCy3)2(Cl)2Ru═CHPh (1) and (IMesH2)(PCy3)(Cl)2Ru═CHPh (2):

In the above molecular structures, “Mes” represents mesityl (2,4,6-trimethylphenyl), “Ph” is phenyl, and “Cy” is cyclohexyl.
Accordingly, there is a need in the art for improved methods of synthesizing olefin macrocycles and their derivatives using catalysts that are tolerant of functional groups and a process that enables precise controls over the resulting products and structural distribution of functional groups in the molecules produced. Ideally, such method would also be useful in the synthesis of novel olefin macrocycles. The invention is directed to such methods, and now provides a highly effective process using a transition metal carbene complex such as (1) or (2). The processes can be used to synthesize expanded olefin macrocycles, in a manner that enables careful control over the macrocycles produced and their properties, as well as derivatives thereof.